Engineering Glucose‐Responsive Insulin Granules with High‐Payload for Long‐Acting Glycemic Control

Abstract Developing high‐payload systems that dynamically respond to physiological fluctuations is crucial not only for improving the precision, safety, and efficacy of protein therapies but also for addressing biosafety concerns associated with carriers, reducing administration frequency, minimizing infection risks, and enhancing patient compliance. However, achieving precise control over protein release in the high‐payload carriers remain a major challenge. In this study, a physiology‐responsive, high‐payload insulin (Ins) granule is engineered for long‐term glucose management, using Ins as a model—an essential hormone that must be released in response to blood glucose changes for effective glycemic control in diabetic patients. The [(Ins&GOx)@Zn]@[TA&Fe] granules achieve an Ins loading capacity (LC%) exceeding 80%, significantly higher than the previously reported maximum of ≈40%. These granules extend the glucose‐regulating effect of free Ins, typically limited to 3 h, to 6 days with a single injection, without any observed risk of hypoglycemia. Long‐term administration (28 days, 4 injection cycles, 7 days injection −1 ) shows no significant physiological toxicity or immune response. This approach offers a promising strategy for developing intelligent, high‐payload delivery systems for protein‐based therapeutics, advancing more precise, safe, and patient‐compliant treatments.